Foreign proteins or DNA, such as genetic material or vectors for gene therapy, or their derivatives, have therapeutic properties and are administered to patients suffering from certain diseases. However, as discussed later, the immunogenicity of the said foreign proteins, nucleotides, DNA or vectors, or of their derivatives, may vitiate the treatment and hence this invention provides an improved method for the treatment of such diseases.
Gene therapy is the insertion of a functioning gene into the cells of a patient (i) to correct an inborn error of metabolism (i.e., genetic abnormality or birth defect resulting in the deficiency of the patient with respect to one or more essential proteins such as enzymes or hormones), or (ii) to provide a new function in a cell (Kulver, K. W., "Gene Therapy", 1994, p. xii, Mary Ann Liebert, Inc., Publishers, New York, N.Y.).
When the host is totally deficient of the inserted gene from birth, the new protein expressed by this gene--when the latter is inserted into the appropriate cell of an adult host--would be expected to induce in the host an immune response against itself. Hence, (i) the host would produce antibodies or cytotoxic cells to the "new" protein, and (ii) this immune response would not only combine and neutralize and thus inactivate the function of the "new" protein, but may also lead to untoward therapeutic complications due to formation of immune complexes. It is, therefore, not surprising that gene therapy has proven successful in adenosine deaminase (ADA) deficiency, i.e., in children deficient of ADA from birth, which is manifested by the absence of functional T lymphocytes and consequently to the severe combined immunodeficiency (SCID) syndrome. The reported success of gene therapy in young children deficient of ADA from birth is related to the immunodeficient status of the child, as no immune response can be generated against the foreign therapeutic genetic material. As a corollary, gene therapy would be successful it it is instituted from birth, when it is relatively easy to induce immunological tolerance to a foreign immunogenic material.
Foreign immunogenic materials, such as biologic response modifiers or their derivatives, often have therapeutic properties and are, therefore, administered to patients suffering from certain diseases. However, as a result of the immunogenicity of the foreign materials, or of their derivatives, for the reasons stated above the insertion of the appropriate gene may vitiate the desired therapeutic effects. This invention provides a method for overcoming this inherent complication due to the immunogenic capacity of the expressed protein, and is therefore considered to represent a novel and an essential improvement for the treatment of such diseases.
As Background to the present invention:
Chen, Y., Takata, M., Maiti, P. K., Mohapatra, S., Mohapatra, S. S. and Sehon, A. H., disclose that the suppressor factor of Ts cells induced by tolerogenic conjugates of OVA and mPEG is serologically and physicochemically related to the .alpha..beta. heterodimer of the TCR. J. Immunol. 152:3-11, 1994.
Mohapatra, S., Chen, Y., Takata, M., Mohapatra, S. S. and Sehon, A. H. disclose "Analysis of TCR .alpha..beta. chains of CD8.sup.+ suppressor T cells induced by tolerogenic conjugates of antigen and monomethoxypolyethylene glycol: Involvement of TCR .alpha.-CDR3 domain in immuno-suppression." J. Immunol. 151:668-698, 1993.
Bitoh, S., Takata, M., Maiti, P. K., Holford-Stevens, V., Kierek-Jaszczuk, D. and Sehon, A. H., disclose that "Antigen-specific suppressor factors of noncytotoxic CD8.sup.+ suppressor T cells downregulate antibody responses also to unrelated antigens when the latter are presented as covalently linked adducts with the specific antigen." Cell. Immunol. 150:168-193, 1993.
Bitoh, S., Lang, G. M., Kierek-Jaszczuk, D., Fujimoto, S. and Sehon, A. H., disclose "Specific immunosuppression of human anti-murine antibody (HAMA) responses in hu-PBL-SCID mice." Hum. Antibod. Hybridomas 4:144-151, 1993.
Bitoh, S., Lang, G. M. and Sehon, A. H., disclose the "Suppression of human anti-mouse idiotypic antibody responses in hu-PBL-SCID mice." Hum. Antibod. Hybridomas 4:144-151, 1993.
Dreborg, S. and Akerblom, E., disclose the safety in humans of "Immunotherapy with monomethoxypolyethylene glycol modified allergens." In: S. D. Bruck (Ed.), CRC Crit. Rev. Ther. Drug Carrier Syst. 6:315-363, (1990).
Generally the term antigen refers to a substance capable of eliciting an immune response and ordinarily this is also the substance used for detection of the corresponding antibodies by one of the many in vitro and in vivo immunological procedures available for the demonstration of antigen-antibody interactions.
Similarly, the term allergen is used to denote an antigen having the capacity to induce and combine with reaginic (i.e., IgE) antibodies which are responsible for common allergies; however, this latter definition does not exclude the possibility that allergens may also induce reaginic antibodies, which may include immunoglobulins of classes other than IgE.
As used herein, the term antigenicity is defined as the ability of an antigen (immunogenic material) or allergen to combine in vivo and in vitro with the corresponding antibodies; the term allergenicity or skin activity is defined as the ability of an allergen to combine in vivo with homologous reaginic antibodies thereby triggering systemic anaphylaxis or local skin reactions, the latter reactions being the result of direct skin tests or of passive cutaneous anaphylactic (PCA) reactions; and the term immunogenicity in a general sense is the capacity of an antigen or allergen, or of their derivatives produced in vitro or processed in vivo, to induce the corresponding specific antibody response.
In relation to this invention, tolerogens are defined as immunosuppressive covalent conjugates consisting of an antigenic material (immunogenic proteins, etc.) and a water-soluble polymer (see e.g. Sehon, A. H., In "Progress in Allergy" (K. Ishizaka, ed.) Vol. 32 (1982) pp. 161-202, Karger, Basel; and U.S. Pat. No. 4,261,973).
In the present context and claims the term tolerogen thus refers to a conjugate consisting of an immunogenic material (protein or polynucleotide) and a nonimmunogenic conjugate, said tolerogen being immunosuppressive in an immunologically specific manner with respect to the antigen which is incorporated into the tolerogenic conjugate irrespective of the immunoglobulin class which is downregulated; furthermore, the tolerogen may comprise a conjugate of an essentially nonimmunogenic polymer and an immunogenic biologically active product or derivative of the genetic material used for gene therapy.
The therapeutic administration of foreign immunogenic material induces an immune response leading to the formation of antibodies of different immunoglobulin classes. Hence, on repeated administration, the material may form complexes in vivo with such antibodies leading to a poor therapeutic effect by virtue of its being sequestered and neutralized by the antibodies, or to anaphylactic reactions by combination with reaginic antibodies, or to other untoward conditions, i.e. immune complex diseases due to the deposition of antibody-antigen complexes in vital tissues and organs.
Wilkinson et al. "Tolerogenic polyethylene glycol derivatives of xenogenic monoclonal immunoglobulins", Immunoloqy Letters, Vol. 15 (1987) pp. 17-22, discloses the criticality of the administration time of a tolerogenic conjugate to a non-sensitized individual at least one day prior to challenge with an antigen.
The present invention overcomes deficiencies of the prior art, providing a means for inducing a priori tolerance to a protein or polynucleotide in an individual deficient of the given protein or polynucleotide, thus making the administration of gene therapy--which involves the generation of immunogenic material in a patient deficient of the corresponding gene--possible and effective.